An expatriate to Ivory Coast (supposedly allergic to artemether-lumefantrine) was diagnosed with severe malaria in Spain. Parasitemia increased from 2% up to 21% within 24 h under quinine (10 mg/kg) and clindamycin (450 mg/8 h) combination treatment. Molecular profiling of the patient revealed the presence of molecular markers of quinine and other antimalarials resistance. Additionally, multiple copies of pfpm2 gene were also noticed in the patient sample, despite the absence of piperaquine drug pressure in Ivory Coast. Parasitemia was cleared with artesunate (2.4 mg/kg) under a desensitization protocol. Nevertheless, detection of early treatment failure is needed mainly in cases of suspected antimalarial resistance.